Kognityvieji sukeltieji potencialai arba su įvykiu susiję potencialai (SĮSP) leidžia įvertinti kai kurias kognityviąsias funkcijas. Jie nuo pat sukūrimo pradžios yra sėkmingai taikomi ir psichikos sutrikimų tyrimuose. SĮSP neinvaziškumas, objektyvumas, saugumas leidžia juos taikyti kognityviųjų funkcijų pokyčių, sukeltų medikamentinio gydymo ar kitos nemedikamentinės terapinės procedūros, įvertinimui. Pagrindinis darbo tikslas buvo įvertinti informacijos apdorojimo klausos sistemoje kitimą atipinių antipsichotikų risperidono ir kvetiapino poveikyje ir nemedikamentinių terapijos metodų - elektros impulsų terapijos bei metaglosoterapijos - poveikyje taikant su įvykiu susijusio potencialo P300 skaitmeninio registravimo ir kiekybinės analizės metodus. Klausos sukeltas P300 potencialas buvo registruojamas taikant „atsitiktinio įvykio“ principą trimis elektrodais (Fz, Cz ir Pz). Buvo matuojami 4 sukeltojo potencialo P300 parametrai: N2 latencija, P300 latencija, P300 amplitudė ir reikšmingo dirgiklio atpažinimo laikas. Darbo rezultatai parodė, kad SĮSP parametrai yra jautrūs informacijos apdorojimo klausos sistemoje procesų pažeidimo šizofrenijos spektro sutrikimų atveju rodikliai. Didesnę teigiamą įtaką klausos sukeltajam potencialui P300 turėjo atipinis antipsichotikas kvetiapinas. Nemedikamentiniai psichikos sutrikimų gydymo metodai nenusileidžia efektyvumu gerinant pacientų kognityviąsias funkcijas medikamentinei terapijai atipiniais antipsichotikais. / Recording and analysis of event-related potentials is safe and harmless method of evaluation of cognition and is suitable to follow the changes of cognitive processes induced by psychoactive drugs or other therapeutic procedures. The main aim of the work was to evaluate the influence of atypical antipsychotics risperidone and quetiapine and such nonpharmacological methods as electroconvulsive therapy and metaglossotherapy on the changes of information processing in the auditory system using event-related potential P300 recording and analysis method. Auditory P300 potential was elicited applying “odd-ball” paradigm and recorded at 3 electrode sites (Fz, Cz, Pz). 4 parameters of P300 potential were measured: N2 latency, P300 latency, P300 amplitude and recognition time of target stimulus. Total number of 85 patients with schizophrenia spectrum disorders and mood disorders were studied. Results of this work showed that the parameters of P300 potential are sensitive indicators of abnormalities of information processing in auditory system in the case of schizophrenia spectrum disorders. More considerable positive influence on the event-related potential P300 had atypical antipsychotic quetiapine and that nonpharmacological methods of treatment of psychiatric disorders are as effective as drug therapy with atypical antipsychotics in remediation of cognitive functions.

Recording and analysis of event-related potentials is safe and harmless method of evaluation of cognition and is suitable to follow the changes of cognitive processes induced by psychoactive drugs or other therapeutic procedures. The main aim of the work was to evaluate the influence of atypical antipsychotics risperidone and quetiapine and such nonpharmacological methods as electroconvulsive therapy and metaglossotherapy on the changes of information processing in the auditory system using event-related potential P300 recording and analysis method. Auditory P300 potential was elicited applying “odd-ball” paradigm and recorded at 3 electrode sites (Fz, Cz, Pz). 4 parameters of P300 potential were measured: N2 latency, P300 latency, P300 amplitude and recognition time of target stimulus. Total number of 85 patients with schizophrenia spectrum disorders and mood disorders were studied. Results of this work showed that the parameters of P300 potential are sensitive indicators of abnormalities of information processing in auditory system in the case of schizophrenia spectrum disorders. More considerable positive influence on the event-related potential P300 had atypical antipsychotic quetiapine and that nonpharmacological methods of treatment of psychiatric disorders are as effective as drug therapy with atypical antipsychotics in remediation of cognitive functions. / Kognityvieji sukeltieji potencialai arba su įvykiu susiję potencialai (SĮSP) leidžia įvertinti kai kurias kognityviąsias funkcijas. Jie nuo pat sukūrimo pradžios yra sėkmingai taikomi ir psichikos sutrikimų tyrimuose. SĮSP neinvaziškumas, objektyvumas, saugumas leidžia juos taikyti kognityviųjų funkcijų pokyčių, sukeltų medikamentinio gydymo ar kitos nemedikamentinės terapinės procedūros, įvertinimui. Pagrindinis darbo tikslas buvo įvertinti informacijos apdorojimo klausos sistemoje kitimą atipinių antipsichotikų risperidono ir kvetiapino poveikyje ir nemedikamentinių terapijos metodų - elektros impulsų terapijos bei metaglosoterapijos - poveikyje taikant su įvykiu susijusio potencialo P300 skaitmeninio registravimo ir kiekybinės analizės metodus. Klausos sukeltas P300 potencialas buvo registruojamas taikant „atsitiktinio įvykio“ principą trimis elektrodais (Fz, Cz ir Pz). Buvo matuojami 4 sukeltojo potencialo P300 parametrai: N2 latencija, P300 latencija, P300 amplitudė ir reikšmingo dirgiklio atpažinimo laikas. Darbo rezultatai parodė, kad SĮSP parametrai yra jautrūs informacijos apdorojimo klausos sistemoje procesų pažeidimo šizofrenijos spektro sutrikimų atveju rodikliai. Didesnę teigiamą įtaką klausos sukeltajam potencialui P300 turėjo atipinis antipsichotikas kvetiapinas. Nemedikamentiniai psichikos sutrikimų gydymo metodai nenusileidžia efektyvumu gerinant pacientų kognityviąsias funkcijas medikamentinei terapijai atipiniais antipsichotikais.

Atypical antipsychotics (AAPs) (also known as second-generation antipsychotics) are the US Food and Drug Administration (FDA) approved medications for schizophrenia, bipolar I disorder, depression and autism. Compared to the typical antipsychotics, AAPs were marketed as reducing adverse side effects such as extrapyramidal symptoms. This resulted in extensive use of AAPs for not only the FDA approved indications but also other conditions that are not approved. However, several post-marketing clinical trials evaluated the use of AAPs and reported serious adverse side effects, including metabolic syndrome, cardiovascular events, or death. The extensive use of AAPs by pediatrics is an important policy problem that imposes serious concerns on public health and economy in the US. A large proportion of total pediatric AAP use is off-label in which the safety and effectiveness are not yet established. Moreover, among the off-label conditions for which AAPs were used, ADHD was the most common primary mental diagnosis. From public health perspective, the risk of type II diabetes in pediatric AAP users was estimated. A retrospective cohort study was conducted and a twice higher risk of developing type II diabetes was estimated for AAP users compared to non-users in pediatrics. From economic efficiency perspective, the cost-effectiveness of AAPs compared to other ADHD medications in pediatric ADHD patients was estimated. Among non-stimulant ADHD medication treatment strategies, AAPs resulted in the lower expected health outcome than other ADHD medications. Also, AAPs were not a favored choice with respect to cost-effectiveness. A comparative effectiveness study that compares resource utilization and costs between atypical antipsychotic (AAP) users and non-AAP users in ADHD revealed that AAP users were likely to visit a healthcare facility for outpatient and inpatient services more frequently than non-AAP users. Total health care costs were significantly higher for AAP users with additional costs of $1,393 (2012 dollars) during six months and $2,784 (2012 dollars) during a year after initiating the AAP treatment.

Introdução O fator neurotrófico derivado do cérebro (BDNF) tem um papel crítico no desenvolvimento e plasticidade neuronal. Acredita-se que a alteração na sinalização do BDNF contribua para a patogênese da esquizofrenia (SZ), especialmente em relação ao déficit cognitivo. Alguns estudos com pacientes esquizofrênicos têm mostrado um efeito benéfico, e outros um efeito prejudicial, da clozapina (CLZ) na cognição. Objetivos O presente estudo tem por objetivo avaliar a associação entre a dose diária de CLZ e os níveis séricos de BDNF em pacientes com SZ. Material e Métodos Foram selecionados dois grupos de pacientes com SZ (n=44) de acordo critério do DSM-IV-TR, cronicamente medicados com CLZ (n=31) e antipsicóticos típicos (n=13). Foram coletados 5ml de amostras de sangue por venopunção. Resultados Os níveis séricos de BDNF foram correlacionados significativamente com a dose diária de CLZ (r=0.394, p=0.028), mas não com a dose diária de antipsicóticos típicos (r=0.208, p=0.496). Conclusão Este estudo sugere que os níveis de BDNF sérico estão correlacionados com a dose diária de CLZ, e que isto deve levar à melhora na cognição observada nos pacientes com SZ tratados com CLZ. Apesar da forte evidência de que a administração crônica de CLZ é efetiva para pacientes com SZ, ainda não se sabe como os antipsicóticos atípicos regulam a expressão do BDNF. A concentração sérica de BDNF na SZ merece futuras investigações, visando o papel das neurotrofinas na resposta cognitiva ao tratamento com CLZ e outros antipsicóticos atípicos. / Introduction Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine (CLZ) has shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. Objectives The aim of the present study was to evaluate the association between CLZ daily dose and serum BDNF levels. Methods Two groups of chronically medicated DSM-IV-TR SZ patients (n=44), on treatment with CLZ (n=31) and typical antipsychotics (n=13) had 5ml blood samples collected by venipuncture. Results Serum BDNF levels were significantly correlated with CLZ daily dose (r=0.394, p=0.028), but not with typical antipsychotic daily dose (r=0.208, p=0.496). Conclusion This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics.

Introdução O fator neurotrófico derivado do cérebro (BDNF) tem um papel crítico no desenvolvimento e plasticidade neuronal. Acredita-se que a alteração na sinalização do BDNF contribua para a patogênese da esquizofrenia (SZ), especialmente em relação ao déficit cognitivo. Alguns estudos com pacientes esquizofrênicos têm mostrado um efeito benéfico, e outros um efeito prejudicial, da clozapina (CLZ) na cognição. Objetivos O presente estudo tem por objetivo avaliar a associação entre a dose diária de CLZ e os níveis séricos de BDNF em pacientes com SZ. Material e Métodos Foram selecionados dois grupos de pacientes com SZ (n=44) de acordo critério do DSM-IV-TR, cronicamente medicados com CLZ (n=31) e antipsicóticos típicos (n=13). Foram coletados 5ml de amostras de sangue por venopunção. Resultados Os níveis séricos de BDNF foram correlacionados significativamente com a dose diária de CLZ (r=0.394, p=0.028), mas não com a dose diária de antipsicóticos típicos (r=0.208, p=0.496). Conclusão Este estudo sugere que os níveis de BDNF sérico estão correlacionados com a dose diária de CLZ, e que isto deve levar à melhora na cognição observada nos pacientes com SZ tratados com CLZ. Apesar da forte evidência de que a administração crônica de CLZ é efetiva para pacientes com SZ, ainda não se sabe como os antipsicóticos atípicos regulam a expressão do BDNF. A concentração sérica de BDNF na SZ merece futuras investigações, visando o papel das neurotrofinas na resposta cognitiva ao tratamento com CLZ e outros antipsicóticos atípicos. / Introduction Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine (CLZ) has shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. Objectives The aim of the present study was to evaluate the association between CLZ daily dose and serum BDNF levels. Methods Two groups of chronically medicated DSM-IV-TR SZ patients (n=44), on treatment with CLZ (n=31) and typical antipsychotics (n=13) had 5ml blood samples collected by venipuncture. Results Serum BDNF levels were significantly correlated with CLZ daily dose (r=0.394, p=0.028), but not with typical antipsychotic daily dose (r=0.208, p=0.496). Conclusion This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics.

Introdução O fator neurotrófico derivado do cérebro (BDNF) tem um papel crítico no desenvolvimento e plasticidade neuronal. Acredita-se que a alteração na sinalização do BDNF contribua para a patogênese da esquizofrenia (SZ), especialmente em relação ao déficit cognitivo. Alguns estudos com pacientes esquizofrênicos têm mostrado um efeito benéfico, e outros um efeito prejudicial, da clozapina (CLZ) na cognição. Objetivos O presente estudo tem por objetivo avaliar a associação entre a dose diária de CLZ e os níveis séricos de BDNF em pacientes com SZ. Material e Métodos Foram selecionados dois grupos de pacientes com SZ (n=44) de acordo critério do DSM-IV-TR, cronicamente medicados com CLZ (n=31) e antipsicóticos típicos (n=13). Foram coletados 5ml de amostras de sangue por venopunção. Resultados Os níveis séricos de BDNF foram correlacionados significativamente com a dose diária de CLZ (r=0.394, p=0.028), mas não com a dose diária de antipsicóticos típicos (r=0.208, p=0.496). Conclusão Este estudo sugere que os níveis de BDNF sérico estão correlacionados com a dose diária de CLZ, e que isto deve levar à melhora na cognição observada nos pacientes com SZ tratados com CLZ. Apesar da forte evidência de que a administração crônica de CLZ é efetiva para pacientes com SZ, ainda não se sabe como os antipsicóticos atípicos regulam a expressão do BDNF. A concentração sérica de BDNF na SZ merece futuras investigações, visando o papel das neurotrofinas na resposta cognitiva ao tratamento com CLZ e outros antipsicóticos atípicos. / Introduction Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine (CLZ) has shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. Objectives The aim of the present study was to evaluate the association between CLZ daily dose and serum BDNF levels. Methods Two groups of chronically medicated DSM-IV-TR SZ patients (n=44), on treatment with CLZ (n=31) and typical antipsychotics (n=13) had 5ml blood samples collected by venipuncture. Results Serum BDNF levels were significantly correlated with CLZ daily dose (r=0.394, p=0.028), but not with typical antipsychotic daily dose (r=0.208, p=0.496). Conclusion This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics.

About 20 to 25 % of psychiatric patients treated with typical antipsychotics may develop an important movement disorder named tardive dyskinesia, with complex etiology and no effective treatment. Cognitive loss is also associated with antipsychotic treatment being harmful and often difficult to identify. Some studies have shown beneficial effects of Omega 3 polyunsaturated fatty acids on tardive dyskinesia and on cognition. Considering the available evidences, we conducted a randomized, double-blind, placebo-controlled, clinical trial, which evaluated the effect of fish oil supplementation rich in n-3 polyunsaturated fatty acids (3 g/dia) or placebo (3 capsules / day), for 12 weeks, on motor and cognitive disturbances of patients on use of neuroleptics. Two evaluations were performed, one before supplementation (baseline) and another at the end of it. For this, were used the following evaluation tools: Abnormal Involuntary Movement Scale for tardive dyskinesia and Mini-Mental State Examination for cognition. Peripheral blood samples were collected before supplementation (baseline) and 4, 8 and 12 weeks after, in order to monitor the supplementation effects on biochemical parameters- triglycerides (TG), fasting glucose, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and on parameters of blood clotting- prothrombin time and partial thromboplastin time. The biological material collected was also used to run the Comet Assay in leukocytes with the aim of investigate the treatment effect on the DNA damage index. After 3 months of supplementation, we observed that fish oil caused an improvement of 18.5 % in tardive dyskinesia, while cognitive performance did not change when compared with the baseline assessment. Furthermore, lipid profile of the patients was not modified, fasting glucose was reduced in all assessments and prothrombin time increased in the last evaluation. In addition, fish oil did not show genotoxic effect (DNA damage index did not change). Therefore, we have demonstrated the therapeutic potential of fish oil rich in Omega 3 on tardive dyskinesia of patients treated with neuroleptics and its low risk of side effects. The increase of prothrombin time suggests a possible anticoagulant effect, requiring its monitoring during chronic treatment. / Cerca de 20 a 25 % dos pacientes psiquiátricos tratados com antipsicóticos típicos podem desenvolver uma importante síndrome motora denominada discinesia tardia (DT), de etiologia complexa e ainda sem tratamento efetivo. Perdas cognitivas também estão associadas ao uso desses medicamentos, sendo muitas vezes de difícil identificação e igualmente prejudiciais. Alguns estudos têm demonstrado efeitos benéficos dos ácidos graxos poliinsaturados Omega 3 (AGPI n-3) sobre a DT e sobre a cognição. Considerando as evidências disponíveis, realizamos este trabalho que consistiu de um ensaio clínico randomizado, duplo-cego, controlado por placebo. Avaliamos os efeitos da suplementação com de óleo de peixe rico em AGPI n-3 (3 g/dia) ou placebo (3 cápsulas/dia) sobre distúrbios motores e cognitivos de pacientes sob uso de neurolépticos, por um período de 12 semanas. Foram efetuadas duas avaliações, uma antes da suplementação (basal) e outra ao final da mesma. Para isso utilizamos as seguintes ferramentas de avaliação: Escala de Movimentos Involuntários Anormais (EMIA), para a DT e Mini-Exame do Estado Mental (MEEM), para a cognição. Amostras de sangue periférico foram colhidas antes da suplementação (basal) e 4, 8 e 12 semanas após, com o propósito de acompanhar seus os efeitos sobre parâmetros bioquímicos- triglicerídeos (TG), glicemia de jejum, colesterol total, colesterol ligado à lipoproteína de alta densidade (HDL-C) e colesterol ligado à lipoproteína de baixa densidade (LDL-C), bem como sobre parâmetros de coagulação sanguínea- tempo de protrombina (TP) e tempo de tromboplastina parcial (TTP). Com o material biológico colhido, também executamos o Ensaio Cometa em leucócitos, para investigar a influência do tratamento sobre o índice de dano no DNA. Após 3 meses de suplementação, observamos que o óleo de peixe produziu uma melhora de 18,5 % na DT, enquanto o desempenho cognitivo não sofreu alteração em relação à avaliação basal. Por sua vez, o perfil lipídico dos pacientes não foi modificado, a glicemia de jejum foi reduzida em todas as avaliações e o TP aumentou na última avaliação. Ainda, o índice de dano no DNA não foi alterado, mostrando que o óleo de peixe não apresentou efeito genotóxico. Com isso, demonstramos o potencial terapêutico do óleo de peixe rico em Omega 3 sobre a DT de pacientes tratados com neurolépticos e seu baixo risco de efeitos colaterais. O aumento do TP sugere um possível efeito anticoagulante, necessitando de acompanhamento durante tratamentos crônicos.

Abstract The aim of this thesis was to explore the associations between the use of nervous system medications and suicidal ideation and behaviour in various different diagnostic groups in a large population-based cohort. Information on prescribed antipsychotic, antidepressant, benzodiazepine and antiepileptic medications within the Northern Finland Birth Cohort 1966 was collected from the register of the Social Insurance Institution of Finland and from a postal questionnaire sent to all cohort members in 1997. The presence of suicidal ideation and depression and anxiety symptoms was assessed via the Hopkins Symptom Checklist-25 questionnaire in 1997. Data on suicides were collected from the cause-of-death statistics and on suicide attempts from the Finnish Care Register for Health Care in a 15-year follow up. The use of antipsychotic, antidepressant, or benzodiazepine medication was associated with increased suicidal ideation, suicide attempts, and suicides. Antiepileptic medication was not associated with increased suicidality. The polypharmacy of nervous system medications was associated with increased suicidality. All nervous system medications were associated with increased severity of depression and anxiety symptoms. When depression and anxiety symptoms were taken into account, most of the associations between medication and suicidal ideation were statistically non-significant. Regarding specific groups, among those who did not have psychosis, high doses of antipsychotic medication correlated particularly with increased suicidal ideation even when other symptoms of depression and anxiety were taken into account. Among those with insomnia, the use of antidepressant medication associated with increased suicidal ideation also when other symptoms were taken into account. Although nervous system medication is associated with increased suicidal ideation, the association with other symptoms is also strong, and therefore it could not be stated that medication associates specifically with suicidal ideation. However, certain groups, i.e., non-psychotic subjects with high doses of antipsychotic medication, or subjects with insomnia and using antidepressant medication, should be closely monitored as they could be more vulnerable to suicidal ideation. / Tiivistelmä Tämän väitöstutkimuksen tarkoituksena oli tutkia hermostoon vaikuttavien lääkkeiden, lähinnä psykoosilääkkeiden, masennuslääkkeiden, bentsodiatsepiinien sekä epilepsialääkkeiden, yhteyttä itsetuhoisiin ajatuksiin, itsemurhayrityksiin ja itsemurhiin. Aihetta tutkittiin eri diagnoosiluokissa suuressa väestöaineistossa, Pohjois-Suomen vuoden 1966 syntymäkohortissa. Tieto tutkimushenkilöiden lääkkeenkäytöstä vuodelta 1997 kerättiin Kelan lääkeostorekisteristä sekä postikyselyn avulla. Itsetuhoisten ajatusten ja muiden masennus- ja ahdistusoireiden vakavuutta mitattiin Hopkins Symptom Checklist-25 -kyselyn avulla vuonna 1997. Tieto itsemurhista kerättiin 15 vuoden seurannassa kuolinsyyrekisteristä ja tieto itsemurhayrityksistä hoitoilmoitusrekisteristä. Psykoosilääkkeiden, masennuslääkkeiden ja bentsodiatsepiinien käyttö oli yhteydessä lisääntyneisiin itsetuhoisiin ajatuksiin, itsemurhayrityksiin ja itsemurhiin. Epilepsialääkkeet eivät liittyneet itsetuhoisuuteen. Usean hermostoon vaikuttavan lääkkeen yhtäaikainen käyttö oli yhteydessä lisääntyneeseen itsetuhoisuuteen. Kaikki hermostoon vaikuttavat lääkkeet liittyivät lisääntyneisiin masennus- ja ahdistusoireisiin. Kun lääkityksen yhteys masennus- ja ahdistusoireisiin otettiin huomioon, lääkkeet eivät olleet erityisesti yhteydessä itsetuhoisiin ajatuksiin. Diagnostisten ryhmien välillä ei ollut eroa hermostoon vaikuttavien lääkkeiden ja itsemurhayritysten tai itsemurhien välisessä yhteydessä. Henkilöillä, joilla ei ole psykoosia, suuremmat psykoosilääkeannokset olivat yhteydessä itsetuhoisten ajatusten vakavuuteen kun muiden masennus- ja ahdistusoireiden vakavuus otettiin huomioon. Unettomuudesta kärsivillä henkilöillä masennuslääkkeen käyttö oli liittyi lisääntyneisiin itsetuhoisiin ajatuksiin kun muut oireet huomioitiin. Hermostoon vaikuttavat lääkkeet ovat yhteydessä lisääntyneisiin itsetuhoisiin ajatuksiin, mutta ne ovat myös vahvasti yhteydessä muihin masennus- ja ahdistusoireisiin. Tietyt henkilöt voivat kuitenkin olla erityisen herkkiä nimenomaan itsetuhoisille ajatuksille, ja heitä tulisi seurata erityisen tiiviisti. Tällaisia ovat henkilöt, joilla ei ole psykoosia, mutta jotka käyttävät suuria psykoosilääkeannoksia, sekä vakavasta unettomuudesta kärsivät henkilöt, jotka käyttävät masennuslääkettä.

Abstract Antipsychotic medication forms the basis of the long-term, even lifelong treatment of schizophrenia. Antipsychotic polypharmacy and adjunctive psychiatric medications are also common treatment strategies. The long-term effects of psychiatric medication, especially on cognition in schizophrenia, are largely unknown. Cognitive impairment is a central, persisting symptomatic feature during the lifespan course of schizophrenia and a key predictor of functional outcome. This naturalistic study aimed to analyse how the lifetime exposure to antipsychotic, benzodiazepine and antidepressant medications, and lifetime trends in antipsychotic use, were associated with cognition in early midlife in schizophrenia. Non-psychotic controls were included as a reference group of normative cognitive performance. The study samples consisted of 40–60 subjects with schizophrenia and 73–191 non-psychotic controls from the Northern Finland Birth Cohort 1966. Data on the lifetime use of medications were collected from medical records, registers and interviews and connected with information from extensive psychiatric and neurocognitive assessments at the ages of 34 and 43 years. Higher cumulative lifetime exposure to antipsychotics was associated with poorer verbal learning and memory at 34 years of age, a decline in verbal learning and memory between the ages of 34 and 43 years and poorer global cognition at the age of 43 years in schizophrenia. A relatively long antipsychotic-free period before the cognitive assessment was associated with better global cognition at 43 years of age. Other lifetime trends in antipsychotic use, antipsychotic polypharmacy or cumulative benzodiazepine or antidepressant exposures were not associated with global cognition. This naturalistic study was the first to report an association between higher cumulative lifetime antipsychotic exposure and poorer cognition in early midlife in schizophrenia, which was not likely confounded by the use of other psychiatric medications or illness-related factors. Though residual confounding is still possible, these results suggest that high-dose long-term antipsychotic treatment may have some influence on the clinical course of schizophrenia, possibly by attenuating cognitive recovery. More research on the long-term effects of psychiatric medications is needed to develop the safe and effective treatment of schizophrenia. / Tiivistelmä Psykoosilääkitys on skitsofrenian pitkäaikaisen, jopa elinikäisen hoidon perusta. Useiden psykoosilääkkeiden yhtäaikaiskäyttö ja muiden psyykenlääkkeiden oheiskäyttö ovat yleisiä hoitostrategioita. Psyykenlääkkeiden pitkäaikaisvaikutuksia etenkin kognitioon skitsofreniassa tunnetaan huonosti. Kognitiiviset puutokset ovat keskeinen, elinaikaisesti pysyvä skitsofrenian oirepiirre ja merkittävimpiä ennustetekijöitä. Tämän naturalistisen tutkimuksen tavoite oli analysoida elinaikaisen psykoosi-, bentsodiatsepiini- ja masennuslääkealtistuksen sekä elinaikaisten psykoosilääkkeiden käytön trendien yhteyttä kognitioon varhaisessa keski-iässä skitsofreniassa. Ei-psykoottiset verrokit toimivat normatiivisen kognitiivisen suorituskyvyn vertailuryhmänä. Tutkimusaineisto koostui Pohjois-Suomen vuoden 1966 syntymäkohorttiin kuuluvista 40 ja 60 henkilöstä, joilla oli skitsofrenia, sekä 73 ja 191 ei-psykoottisesta verrokista. Tiedot psyykenlääkkeiden elinaikaiskäytöstä kerättiin sairauskertomuksista, rekistereistä ja haastatteluista, ja ne yhdistettiin 34 ja 43 vuoden iässä tehtyihin laajoihin psykiatrisiin ja neuropsykologisiin tutkimuksiin. Korkeampi kumulatiivinen elinaikainen psykoosilääkealtistus oli yhteydessä heikompaan kielelliseen muisti- ja oppimissuoriutumiseen 34-vuotiaana ja sen suurempaan laskuun 34 ja 43 ikävuoden välillä sekä heikompaan kognitioon 43-vuotiaana skitsofreniassa. Suhteellisen pitkä psykoosilääketauko ennen neuropsykologista tutkimusta oli yhteydessä parempaan kognitioon 43-vuotiaana. Muut elinaikaisen psykoosilääkityksen käytön trendit, psykoosilääkkeiden yhtäaikaiskäyttö tai elinaikainen kumulatiivinen bentsodiatsepiini- tai masennuslääkealtistus eivät olleet yhteydessä kognitioon. Tämä naturalistinen tutkimus kuvasi ensimmäisenä yhteyden suuremman kumulatiivisen elinaikaisen psykoosilääkealtistuksen ja heikomman kognition välillä varhaisessa keski-iässä skitsofreniassa. Muiden psyykenlääkkeiden käyttö tai sairauteen liittyvät tekijät eivät näyttäneet sekoittavan tätä yhteyttä. Vaikka on mahdollista, että kaikkia sekoittavia tekijöitä ei pystytty huomioimaan, tulosten perusteella korkea-annoksinen, pitkäaikainen psykoosilääkitys saattaa vaikuttaa skitsofrenian taudinkulkuun heikentämällä kognitiivista toipumista. Lisätutkimusta psyykenlääkityksen pitkäaikaisvaikutuksista tarvitaan skitsofrenian turvallisen ja tehokkaan hoidon kehittämiseksi.

Diese Arbeit beschreibt Ergebnisse einer in-vitro Untersuchung der Antipsychotika Chlorpromazin, Haloperidol, Clozapin, N-Desmethylclozapin und Quetiapin bezüglich ihrer Wirkung auf die Zytokinproduktion. Dafür wurde Vollblut von gesunden Probandinnen invitro mit dem Immunmodulator Toxic-Shock-Syndrome-Toxin-1 (TSST-1) stimuliert. Dabei wurden die Konzentrationen der Zytokine Interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-17 und Tumornekrosefaktor-α (TNF-α) im unstimulierten Blut und im stimulierten Blut, jeweils mit und ohne Zusatz der Antipsychotika gemessen. Es zeigte sich, dass TSST-1 eine signifikante Stimulation der Produktion aller getesteten Zytokine bewirkte und dass es über diese Stimulation mit TSST-1 hinaus zu einer Erhöhung von IL-17 unter allen getesteten Antipsychotika kam. Aufgrund dieser Ergebnisse ist es denkbar, dass Antipsychotika, in Ergänzung zu ihrer Wirkung an Dopaminrezeptoren, auch über diese immunologische Eigenschaft Wirkungen und Nebenwirkungen entfalten können. Weiterhin könnte die IL-17-Produktion ein Biomarker in der Behandlung mit Antipsychotika sein, der wiederum zur individuellen Vorhersage von Wirkungen und Nebenwirkungen beitragen könnte.